Substituted aminoethyl indoles

ABSTRACT

THIS INVENTION DESCRIBES NEW SUBSTITUTED INDOLE COMPOUNDS. INTERMEDIATE 3-HALODICARBONYL INDOLES ARE ALSO DESCRIBED. THE PREPARATION OF THE FINAL PRODUCTS FROM THE 3-HALODICARBONYL INDOLES WHEREIN THE 3-POSITION CONTAINS A DISUBSTITUTED B-AMINOETHYL GROUP IS DESCRIBED. THE COMPOUNDS HAVE UTILITY AS CENTRAL NERVOUS SYSTEM DEPRESSANTS, ANALGESICS, ANTI-INFLAMMATORY AGENTS, AND DIURETIC AGENTS.

United States Patent Ofiice v 3,686,213 SUBSTITUTED AMINOETHYL INDOLES John Frank Poletto, Nanuet, N.Y., and George Rodger Allen, .llr.', 011d Tappan, Ruddy Littell, River Vale, and Martin Joseph Weiss, Oradell, N.J., assignors to American Cyanamid Company, Stamford, Conn.

No Drawing. Continuation-impart of application Sen N0. 1,045, Jan. 6, 1970, which is a continuation-in-part of application Ser. No. 603,772, Dec. 22, 1966. This application Aug. 28, 1970, Ser. No. 68,005

Int. Cl. C07d 27/56 US. Cl. 260--326.15 9 Claims ABSTRACT OF THE DISCLOSURE This invention describes new substituted indole compounds. Intermediate 3-halodicarbonyl indoles are also described. The preparation of the final products from the 3-halodicarbonyl indoles wherein the 3-position contains a disubstituted B-aminoethyl group is described. The compounds have utility as central nervous system depressants, analgesics, anti-inflammatory agents, and diuretic agents.

a Rs wherein R is hydrogen or a lower alkyl group; R R and R are lower alkyl groups, R being substituted at the 4-, 6- or 7-position of the indole nucleus; R is a member of the group consisting of lower alkyl, lower alkenyl, omega-hydroxy lower alkyl, and benzyl; R is a member of the group consisting of lower alkyl, lower alkenyl, and omega-hydroxy lower alkyl;

taken together is a member of the group consisting of omega-lower alkylthio lower alkylamino, pyrrolidino, piperidino, morpholino, homopiperidino, 3,6ethanohomopiperidino, 3,7-methanoheptamethyleneimino, lower alkylpiperidino, 4,4 spirocyclohexylpiperidino, 2,5-ethanopiperidino, phenylpiperidino, 2 lower alkyl-2-pr0peneamino, 3-pyrrolinyl, 1,2,5,6-tetrayhdropyridino, 2,2,2-trilluoroethylamino, and 2-propeneamino; and pharmaceutically acceptable acid addition salts.

The term lower alkyl includes those alkyl groups having 1 to 6 carbon atoms and the term lower alkenyl also includes those alkenyl groups of 2 to 4 carbon atoms. Pharmaceutically acceptable acid addition salts may include hydrochlorides, hydrobromides, sulfates, nitrates, maleates, fumarates, succinates, tartrates, and the like.

In the present invention a group of compounds of particular importance for their antifiammatory activity are compounds of the formula:

3,686,213 Patented Aug. 22, 1972 wherein R is hydrogen or lower alkyl; R R R R and R7, 3 l'e lower alkyl, R is substituted at the 4-, 6- or 7- positlon of the indole ring;

taken together is morpholino, pyrrolinyl, 1,2,5,6-tetrahydropyridyl, 2-lower alkyl piperidino, 2,5-ethanopiperidino, homopiperidino, 3,6 ethanohomopiperidino, 3,7- methanoheptamethyleneimino and pharmaceutically acceptable acid addition salts thereof.

The compounds of this invention can be obtained by the following reaction sequence.

FLOWSHEET H0 4102mm H01 no l l l N -Rz v N '-Ra Ra Rs I 0 M 0-01 t t l 0 R1O "COCl Rio 0-01 1 R R f N Rs I By /R4 in 0 R4 R10 (JJ("}N/ I R5 R III/R2 \LlAlHi /R4 R 0-| CHa-CHr-JN kl \RE N a s l wherein R R R R and R are as defined above.

The l-alkyl compounds can be prepared by treatment with a base followed by an alkylating agent.

It is also possible to obtain the 4-methyltryptamine derivatives (VI, R =4-methyl) by appropriate lithium aluminum hydride reduction of the corresponding 4-trifluoromethylglyoxylamide (V, R =4-CF as described in the patent referred to above. In this instance, when the 4-trifiuoromethylamide is heated, preferably for at least 48 3 hours in refluxing tetrahydrofuran, with lithium aluminum hydride not only is the glyoxylamide reduced to the 8-aminoethyl side chain of (VI), but in addition, the 4- trifluoromethyl group undergoes hydrogenolysis to the 4- methyl grouping.

The tryptamine derivatives of this invention are white, crystalline substances recrystallizable from the usual organic solvents. The compounds represented by Formula VI above are sufficiently basic to form acid-addition salts as indicated hereinbefore.

Compounds of this invention have activity in warmblooded animals as CNS depressants, analgesics, tranquilizers, diuretic agents and anti-inflammatory agents. These effects in warm-blooded animals are evidenced at doses within a range of from 1.0 mg. to 30 mg. per kilogram of animal body weight per day. Preferably a dosage range of 5 to 20 mg. per kilogram of body weight per day is used.

The central nervous depressant properties of the compounds of the present invention are indicated by several procedures. For example, a test which indicates hypnotic and/ or muscle relaxant type activity is represented by the rod walking test, a description of which follows. Groups of 6 mice each are tested for their ability to walk across a horizontal rod in a normal manner after receiving graded doses interperitoneally of a test compound. A median effective dose of the said compound is then estimated.

Another test which indicates tranquilizing activity in warm-blooded animals is represented by a measure of the reduction in motor activity. This is determined by administration of a candidate compound to a group of 5 mice and a 5 minute count of motor activity (recorded with the use of a photoelectric counter). Counts of 250 or less are considered to indicate a specific reduction statistically (more than two standard derivations) of motor activity. Compounds that appeared to reduce motor activity (equal to or less than 250 count) are administered to additional groups of 5 mice and tested similarly. The dose (MDD) which causes a 50% reduction of motor activity (a count of about 250) is estimated. The use of reduced motor activity as a measure of tranquilizing activity has been described by W. D. Gray, A. C. Osterberg and C. E. Rauh, Archives Internationales de Pharmacodynamic et de Therapie, vol. 134, p. 198 (1961) and W. J. Kinnard and C. J. Carr, Journal of Pharmacology and Experimental Therapeutics, vol. 121, 354 (1957). The following Table I summarizes the activity of some of the present compounds.

TABLE I.-TRANQUILIZING ACTIVITY Rod walking Compound: dose, mg./kg.

2,4 dimethyl 5 methoxy-N,N-dimethyltryptamine 28 2,7 dimethyl 5 methoxy N,N dimethyltryptamine 26 2,7 dimethyl 5 methoxy N,N-diethyltryptamine 22 2,7 dimethyl 5 methoxy N,N dipropyltryptamine 25 2,4 dimethyl 5 methoxy N (2 methyl- 2-propenyl)tryptamine 76 2,7 dimethyl 5 methoxy N isopropyl N- hydroxyethyl-tryptamine 42 2,7 dimethyl 5 methoxy N ethylthio-ethyltryptamine 68 1U? (2,4 dimethyl 5 methoxy indolyl 3) ethyl]pyrrolidine 58 Ins-(2,7 dimethyl 5 methoxy indolyl 3) ethyl]pyrrolidine 18 1[fl (2,7 dimethyl 5 methoxy indolyl 3) ethyl]piperidine 14 lm (2,7 dimethyl 5 methoxy-indolyl 3) ethyl1morpholine 86 4 TABLE IContinued Rod Walking Compound: dose, mg./kg.

l[B (2,7 dimethyl 5 methoxy-indolyl-3) ethyl]homopiperidine 20 l[B (2,7 dimethyl 5 methoxy-indolyl-3) ethyl]-3-methylpiperidine 34 1[;3 (2,7 dimethyl 5 methoxy-indolyl-3) ethyl]-4-phenylpiperidine 68 1[B (2,4 dimethyl 5 methoxy-indolyl-3) ethyl]-3-pyrroline 50 2,7 dimethyl 5 methoxy N(2 methyl 2- propenyl)tryptamine 68 l[,8 (2,7 dimethyl 5 methoxy-indolyl-3) ethyl]-3-pyrroline 68 2,7 dimethyl 5 methoxy N,N dipropenyl- Z-tryptamine 52 1[fl (2,4-dimethyl 5 methoxy-indolyl-3) ethyl]-3,6-ethanohomopiperidine 94 Diuretic activity was determined as follows. Mature male rats Weighing between and 300 grams were allowed a normal fluid intake prior to testing. A single oral administration of the test compound was given in 0.5 milliliter of 2% aqueous starch suspension. Four cages (2 rats per cage) served as controls for each measurement. Control animals received only the starch suspension. After administration, the test animals were placed in metabolism cages and observations of the amount of urine excreted were made after 5 hours and after 24 hours. These urine measurements were then adjusted to compensate for differing weights of individual animals. The final values recorded were the ratio of the adjusted amount of urine excreted by the test rats to the adjusted amount of urine excreted by the test rats to the amount of urine excreted by the control rats. Statistical procedures as described by Cummings, J. R. et al., A Sequential Probability Ratio Method for Detecting Compounds with Diuertic Activity in Rats, J. Pharmacol. Exptl. Therap. 128: 414-418 (1960), were used to evaluate the test results of the compounds tested.

For determination of diuretic activity in dogs, compounds were tested using the method of J. M. Little and C. Cooper, Jr., Fed. Proc. 9: 296 (1950). Briefly described, dogs were given 35 ml./kg. of water by gavage, deprived of food and water, catheterized 16 hours later, and given an additional 25 mg./ kg. of water plus a gelatin capsule of the test compound. The animals were returned to their metabolism cages and observations of the amount of urine excreted were made after 6 hours and after 24 hours. Statistical procedures were used to evaluate the test results of the compounds tested.

Anti-inflammatory tests on rats are conducted on groups of two rats each, injected subcutaneously at the midline of the shaved sacral region with 0.5 m1. of an aqueous 2% carrageenin solution. Carrageenin is a polygalactose sulfate extracted from Irish moss, a type of seaweed. Subcutaneous injection of carrageenin causes rapid formation of an intense subcutaneous inflammatory reaction which develops into a connective tissue granuloma. The test compounds of this invention are suspended in aqueous 1% starch-sodium phosphate butter solution, pH 6.5, and administered by oral tubing in 0.5 ml. of said buffer; the total dose for each animal in 250 mg./kg. of body weight. One-half of each total dose is administered immediately following the carrageenin injection and the other half of each total dose is administered 4 hours later. Alternatively, the total dose for each animal may be administered all at once immediately following the carregeenin injection. The animals are sacrificed 24 hours after the carrageenin injection. The inflammatory reaction to the carrageenin initiates the formation of exudate and gelatinous material which is removed and weighed. Control animals receive the carrageenin injection and the starch-sodium phosphate buffer solution orally without the test compound. Critical ratios, i.e., the

(C/Tratio) Stage Reject Accept 1. (C/T) l.ll 1.65 2. (CIT), x(C/T)2 1.49 223 )1 )2 (C/T)a 2. 46 2. 46

Thus, a compound which on the first stage gives a (C/T) =1.11 or below is rejected; it the ratio is between 1.11 and 1.65, the compound is retested; and if the ratio is 1.65 or above the compound is accepted as active. On the second stage (retest because (C/T); is between 1.11 and 1.65) if the product (C/T) (C/T) is 1.49 or below the compound is rejected; if the product is between 1.49 and 2.23, the compound is retested; and if the product is 2.23 or above, the compound is accepted as active. On the third stage, if the product (C/T) (C/T) (C/T) is less than 2.46 the compound is rejected as inactive; but if this product is 2.46 or above, the compound is accepted as an active antiinflammatory agent.

The following examples describe in detail the preparation of representative compounds of the present invention and denote in many instances the activities found.

EXAMPLE 1 Preparation of 2,7-dimethyl--hydroxyindole A mixture of 24.5 g. of ethyl 2,7-dimethyl-5-hydroxyindole-3-indolcarboxylate (Chemistry and Industry, 1965, 2096) and 750 ml. of 20% hydrochloric acid solution is heated at reflux temperature under nitrogen for 2 hours. The resulting solution is cooled, its pH is adjusted to 6.5, and is then extracted with ethyl acetate. The extract is dried and concentrated and the residue is crystallized from methylene chloride. This procedure gives 6.97 g. of white crystals, melting point 144-146 C.

EXAMPLE 2 Preparation of 2,7-dimethyl-S-methoxyindole A magnetically stirred solution of 6.58 g. of 2,7-dimethyl-S-hydroxyindole (Example 1) in 73 ml. of ethanol and 147 ml. of 2 N sodium hydroxide is heated, under nitrogen, with 18 ml. of methyl sulfate and the mixture is heated at reflux temperature for 1 hour. The cooled mixture is diluted with water and extracted with ethyl acetate. This extract is washed with water, dried, and concentrated and the residue is purified by adsorption chromatography on a magnesia-silica gel column. This procedure gives 5.99 g. of yellow crystals, melting point 69-71 C.

EXAMPLE 3 Preparation of 2,6-dimethyl-5-hydroxyindole Treatment of ethyl 2,6-dimethyl-S-dimethyl-S-hydroxyindole-3-carboxylate (Chemistry and Industry, 1965, 2096) by the procedure described in Example 1 gives white crystals, melting point 177-181 C.

EXAMPLE 4 Preparation of 2,6-dimethyl-S-methoxyindole Treatment of 2,6-dimethyl-S-hydroxyindole (Example 3) by the procedure described in Example 2 gives white crystals, melting point l-103 C.

EXAMPLE 5 Preparation of 2,6-dimethyl-S-ethoxyindole Treatment of 2,6-dimethyl-5-hydroxyindole (Example 3) with diethylsulfate by the procedure described in Example 2 gives light yellow crystals, melting point 120- 121 C.

EXAMPLE 6 Preparation of 2,7-dimethyl-S-ethoxyindole Treatment of 2,7-dimethyl-S-hydroxyindole (Example 1) with diethylsulfate by the procedure described in Example 2 gives light yellow crystals, melting point 90- 10 93 C.

EXAMPLE 7 Preparation of ethyl 2-ethyl-4-chloro-5-hydroxy-7-methylindole-3-carboxylate A solution of 5 g. of 5-chloro-2-methyl-1,4-benzoquinone [Journ. Chem. Soc., 755 (1952)] is treated drop wise with 4.58 g. of ethyl 3-amino-2-pentenoate under nitrogen. The solution is stirred at room temperature for 30 minutes and then is heated at 78-80 C. for forty-five minutes. The reaction mixture is cooled and extracted with ethyl acetate. This extract is washed with water, dried and concentrated. The residue is purified by adsorption chromatography on a magnesium-silica gel column. This procedure gives 3.173 g. of off-white crystals, melting point l-125 C.

EXAMPLE 8 Preparation of ethyl 2-ethyl-4-chloro-5-methoxy-7- methylindole-3-carboxylate Treatment of ethyl 2-ethyl-4-chloro-5-hydroxy-7-meth ylindole-B-carboxylate (Example 7) with dimethyl sulfate by the procedure described in Example 2 gives White crystals, melting point 143145 C.

EXAMPLE 9 Preparation of 2-ethyl-4-chloro-5-methoxy-7-methylindole A mixture of 500 mg. of ethyl 2-ethyl-4-chloro-5-methoxy-7-methylindole-3-carboxylate (Example 8) 1.07 g. of potassium hydroxide and 5 m1. of 95% isobutyl alcohol is heated at reflux temperature for forty-eight hours. The reaction mixture is cooled and diluted with 40 ml. of water and extracted with ether. The ether is washed with saline, dried and concentrated and the residue is chromatographed on silica gel and eluted with benzine to give the product as off-white crystals, melting point 100-102 C.

EXAMPLE 10 Preparation of 2-ethyl-5-methoxy-7-methylindole A mixture of 3 g. of 2-ethyl-4-chloro-5-methoxy-7- methylindole (Example 9), 2.63 g. of potassium acetate,

3.22 g. of 10% palladium-on-charcoal in 200 ml. of ethanol is shaken in a Parr low pressure hydrogenator apparatus at an initial hydrogen pressure of 30 p.s.i. until hydrogen uptake ceases. The reaction mixture is filtered and concentrated. The residue is partitioned between methylene chloride and water. The organic phase is separated and washed with water, dried and evaporated to give 2.418 g. of a yellow oil; melting point of picrate salt 119- 120" C.

EXAMPLE 11 Preparation of t-butyl 3-aminocrotonate A stream of ammonia gas is bubbled into 100 g. of tbutyl acetoacetate for 6 hours while the temperature is maintained at 45 C. The aqueous layer is separated and the organic phase is distilled at 72-75 C. and 2 millimeters of mercury. The product, colorless crystals, melting point 33-35 C., is recrystallized from hexane to give melting point 37-39 C.

EXAMPLE 12 Preparation of t-butyl S-hydroxy-2-methyl-4-trifluoromethylindole-3-carboxylate A solution of 8.75 g. of trifluoromethyl-p-benzoquinone 75 and 7.85 g. of t-butyl 3-aminocrotonate in 40 ml. of etha- 1101 is heated at reflux temperature for 30 minutes. After the addition of 100 ml. of benzene and 40 ml. of heptane, 80 ml. of solvent is distilled from the mixture which is cooled and filtered to give a tan powder, melting point 218-220 C. (decomposition). The product may be purified by sublimation to give white crystals, melting point 225-227 C. (decomposition).

EXAMPLE 13 Preparation of t-butyl -methoxy-2-methyl-4-trifiuoromethylindole-3-carboxylate A solution of g. of S-hydroxy-2-methyl-4-trifluoromethylindole-3-carboxylate and 4.0 g. of dimethyl sulfate in 125 ml. of acetone containing 9.0 g. of anhydrous potassium carbonate is heated at reflux temperature for 3 hours. The solids are removed by filtration and the filtrate is evaporated. The residue is crystallized from benzene-hexane to give white needles, melting point 190192 C. The product may be sublimed to give white crystals, melting point l88l9l C.

EXAMPLE 14 Preparation of 5-methoxy-2-methyl-4- trifluoromethylindole A solution of 7.0 g. of t-butyl 5-methoxy-2-methyl-4- trifluoromethylindole-3-carboxylate and 600 mg. of ptoluenesulfonic acid in 400 ml. of toluene is heated at reflux for 1 hour. After cooling, the purple solution is Washed with water, dried with magnesium sulfate and evaporated to give a deep red oil. The oil is dissolved in ether, passed through a pad of silica gel and concentrated with n-hexane to give the product as white needles, melting point 122-125 C. (decomposition).

EXAMPLE 15 Preparation of S-methoxy-2,4-dimethylindole A solution of 500 mg. of S-methoxy-2-methyl-4-trifluoromethylindole in 75 ml. of tetrahydrofuran containing 500 mg. of lithium aluminum hydride is heated at reflux temperature for 48 hours. After cooling, the hydride is decomposed with water and the inorganic residue is removed by filtration. The filtrate is evaporated, dissolved in ether, washed with water, dried, and again evaporated. The crude residue is chromatographed on silica gel and eluted with methylene chloride-n-hexane (6:5) to give the product as a tan solid, melting point 50 C. The product may be sublimed to give white, fluffy crystals, melting point 54-55 C.

EXAMPLE 16 Preparation of 2,7-dimethyl-5-methoxyindole-3-glyoxylic acid chloride and 2,7-dirnethyl-5-methoxyindole-3-N,N- dimethylglyoxylamide A solution of 2.0 g. of 2,7-dimethyl-S-methoxyindole (Example 2) in 70 ml. of ether at 0 C. is treated dropwise with 1.72 ml. of oxalyl chloride in 5 ml. of ether. The mixture is stirred for 30 minutes and then filtered. The yellow solid (2,7-dimethyl-5-methoxyindole-3-gly0xylic acid chloride) thus obtained is added portionwise to 40 ml. of ice cooled aqueous dimethylamine. After minutes the resulting mixture is filtered. This procedure gives 1.40 g. of N,N-dimethylamide as white crystals, melting point 252-254 C.

EXAMPLE 17 Preparation of 2,6-dimethyl-5-methoxyindole-3-glyoxylic acid chloride Treatment of 2,6-dimethyl-S-methoxyindole (Example 4) with oxalyl chloride by the procedure of Example 16 is productive of 2,6-dimethyl-5-methoxyindole-3-glyoxylic acid chloride.

8 EXAMPLE 18 Preparation of 2,4-dimethyl-5-methoxyindole-3-glyoxylic acid chloride Treatment of 2,4-dimethyl-5-methoxyindole with oxalyl chloride by the procedure of Example 16 gives 2,4- dimethyl-S-methoxyindole-3-glyoxylic acid chloride.

EXAMPLES 19-64 By the procedure of Example 16, 2,7-dimethyl-5- methoxyindole-3-glyoxylic acid chloride (Example 16), 2,6-dimethyl 5 methoxyindole-3-glyoxylic acid chloride (Example .17), or 2,4-dimethyI-S-methoxyindole-3-glyoxylic acid chloride (Example 18), is treated with the appropriate amine to give the corresponding 2-(4-, 6 or 7)- dimethyl-S-methoxyindole-3-glyoxamides of Table II as follows:

TABLE II.-2-(4-, 6 or 7)-DIMEIHYL5-METHOXYINDOLE3 GLYOXYLAMIDES moo-m 0000121 I X N CH3 R Melting R R I point, C.

19 4-CH CH 149-150 20 (3-0113 Same as above Oil 21 7-CH3 CzHs 184-185 CgHg 22 4-CH; 03H? -161 23 7-CH3 Same as above 161-164 25 7-0113 Same as above 101-192 27 G-CH: Same as above 247-250 28 7-CH; do 113-116 32 G-CH; Same as above 290-293 33 7-CHa do 220-222 34 7-011 Oil 36 7-CHs Same as above -195 38 6-CH3 Same as above 238-240 30 7-CH; 234-244 See footnotes at end of table.

TABLE II-Cntinued Melting R R point, e O.

4- H0 BI 206-208 I ICH1O=CH:

41 fi-GH; H 205-207 I I-CHr-C=CH,

42 7-011; Same as above 163-165 43 7-011, H 181-182 l ICHaCH=CH:

44 4-CH3 03H;

N-CHz-CH=CH:

45 7-CH Same as above 173-174 NCHg-CH=CH 4s 7-CH: 255-257 7-CH; CHiCH=CHz 181-182 CHaCH=CH:

50 7-OH; H 118-120 I I-CHz-CH CH 51 7-CHs 196-198 I ICHaCH=CHg 52 4-CH OHCH=CH 110-112 OHzCH=OHn 53 7-CHa H 201-202 Ill-CH CF; 54 7-CH: II 80-85 I!I-CH1 CHa-S 01H;

55 7-011 CH; Glass N CH:

H CHa 56 6-0113 CHaCHa 179-180 N'CH3CHa 57 7-CH1 C'Hr-CHPOH 160-162 N-CHz-CHn-OH 58 7-CH; H CH1 Oil O N CH (iiHr-CHz-OH 60 G-CH: Same as above 190-192 Ha -.-.-do 214-215 9 CH CH;

64 7-CHs 185-190 Softens. Melts.

EXAMPLE 65 Preparation of 2,6-dimethyl S ethoxyindole-3-glyoxylic acid chloride and 2,6-dimethyl-S-ethoxyindole-3-N,N- dimethylglyoxylamide Treatment of 2,6-dimethyl-5-ethoxyindole (Example 5) with oxalyl chloride by the procedure described in Example 1-6 gives 2,6-dimethyl-5-ethoxyindole-3-glyoxylic acid chloride and treatment of this acid chloride with dimethylamine by the procedure of Example 1 6 gives 2,6- dimethyl 5 ethoxyindole-3-N,'N-dimethylglyoxy1amide as white crystals, melting point 177-179" C.

lEXAMPLE 66 Preparation of 2,7-dimethyl-5-methoxy-N,N-dimethyltryptamine A suspension of 1.1 g. of 2,7-dimethyl-5-methoxyindole-3-N,N-dimethylglyoxylamide (Example 16) in ml. of tetrahydrofuran is treated portionwise with 1.53 g. of lithium aluminum hydride. The mixture is heated at reflux temperature for 48 hours, cooled and treated with 10 ml. of saturated sodium potassium tartrate solution. Crystallization from ether of the solid which forms affords 656 mg. of 2,7-dimethyl-5-methoxy-N,'N-dimethyltryptamine tartrate as white crystals, melting point EXAMPLES 67-109 Submission of the appropriate 2,(4, 6 or 7)-dimethyl- 5-methoxyindole-3-glyoxylamides (Table II) to treatment with lithium aluminum hydride by the procedure described immediately above in Example '66, gives the 2,(4, 6 or 7)-dimethyl-S-methoxytryptamines of Table III below. If necessary, other acids, such as maleic and succinic, can be substituted for the tartaric acid of Example 66 to give the corresponding amine acid addition salts.

TABLE III.-2, (4, 0 or 7)-DIME'IHYL-5-METHOXYTRYPT- AMINES N R l Melting point, R 1 C. (salt) Examples:

CzHg;

68 4-CH3 /CH2CH2OH 2 170-172 CHZCHQCH! 69 7-CH Same as above I 141-144 70 4-CHs /CHa 133-135 71 G-CH; Same as above 150-151 72 6-CHa CHaCHa -137 CHaCHa 73 7-CH3 /CH(CH;1)1 220-222 CHz-CH:OH

NOH:-CHg- CH3OHr-S See footnotes at end of table.

12 TABLE III-Continued TABLE IIICnt111ued Melting Melting point, point, R R, 0. (salt) R R 0. (salt) 75 4-011, 120-122 5 103 7-cHs I?! 172-175 NCH1CH=CH1 76 'l-CH; Same asabove 121-122 104 6-CH 0 121-123 77 7-0Hs CHzCHaOH 011 N 10 105 7-0Hs I 242-243 78 4-011; 156-158 cmcHs 106 7-CH3 O 189-193 Same as above 150-152 (Z 4 126-128 N 107 7-cHs D 122-123 N Same as above I 163-155 Same as above 1 137138 108 7-CH; N/ 3 190-1 2 6 127-129 109 7-CHs CH1 120-123 "183-184 /CHa H CH1 s5 GCH Q 146 148 I Maloate; 1 Suecinate; 8 Fumarate; 4 Free base; 5 Homifumarato.

"""" a The compounds of Examples 67, 71,72, 73, 76, 79, 81, N s2, s3, s5, 86, 87, 88 90, 92, 93, 95, 98, 100, 102, 103,

\ 104, 10s and 107, show analgesic activity.

The compound of Example 88 shows anti-depressant 86 7-CHs Same as above 110-113 activity. 87 mm The compounds of Examples 71, 81, 83, 85, 86, 95, 96, N 39 105, 106, 107 and 108 show anti-inflammatory activity.

The compounds of Examples 66, 67, 71, 72, 73, 76, 79, CH; 81, 85, 86, 87, 90, 92, 93 ,96, 98, 100, 104 106, and 108 88 7 CHa show diuretic activity.

1 EXAMPLE 110 so 4-011; G 1100-1 Preparation of 2,6-dimethyl-5-ethoxy-N,N-dimethyltryptamine Treatment of 2,6 dimethyl-S-ethoxyindole-3-N,N-dimethylglyoxylamide (Example 65) by the procedure de- 90 7 CH3 same as above 9H5 scribed in Example 66 gives an oil. This oil forms with 91 167-169 maleic acid, a maleate salt, melting point 190193 C. N\ This compound shows anti-inflammatory, analgesic, and diuretic activity. CH =C=CH (EH EXAMPLE 111 Preparation of 3-[2-(2,7-dimethyl-5-ethoxy-3-indolyl) 35:31:: 852 fifiiffiifif'fit1i1:::::::: 05 122 yn-sz y 13.2.21n na 94 1 127-129 By the procedure of Example 16, 5-ethoxy-2,7-dimethylindole (Example 6) is treated with oxalyl chloride and the resulting S-ethoxy 2,7 dimethylindole-3-glyoxylic 3g 98% Sam as 182485 acid chloride is treated with 3-azabicyclo[3.2.2]nonane by the procedure of Example 16 to g1ve the correspondmg 3- 97 /CH1CH=CH1 glyoxamide derivative (melting point 242-243 C.) which N is then reduced with lithium aluminum hydride by the \CHaCH=CH, procedure of Example 66 to provide the subject compound as the maleate salt with melting point at ZOO-202 C. 98 Same as This compound shows analgesic activity.

4-0111 /CH2CH1 EXAMPLE 112 65 Preparation of 3-[2-(ethyl-7-methyl-5-methoxy-3-indolyl) CH10H=CH1 ethyl]-3-azabicyclo[3.2.2]nonane Same as -112 By the procedure of Example 16, 2-ethyl-5-meth0xy-7- 101 7-CH CH; 011 methylindole (Example 10) is treated with oxalyl chloride and the resulting 2-ethyl-5-methoxy-7-methylindole-3- gly- 7O oxylic acid chloride is treated with 3-azabicyclo[3.2.2] Q nonane by the procedure of Example 16 to give the corresponding 3-glyoxamide derivative (melting point 193- 102 168470 195 C.) which is then reduced with lithium aluminum N-cHs-cF 7 hydride by the procedure of Example 66 to provide the subject compound with melting point at 108-110 C. after 13 recrystallization from ether-petroleum ether (boiling point 30 60" C.)

This compound has activity as an analgesic agent.

EXAMPLE 113 Preparation of -chloro-2-ethyl-1,4-benzoquinone This quinone is prepared by addition of hydrogen chloride gas to ethyl-1,4-benzoquinone according to the procedure of Burton and Praill, Jour. Chemical Soc. 755 (1952)] followed by silver oxide oxidation in accordance with the procedure [H. H. Hodgson and F. H. Moore, Jour. Chemical Soc., 2036 (1926)] described for the preparation of the corresponding 5-chloro-2-methyl-1,4-benzoquinone. The yield is 42%, melting point 65-66 C.

EXAMPLE 114 Preparation of t-butyl 4-chloro-7-ethyl-5-hydroxy-2- methylindole-3-carboxylate EXAMPLE 1 15 Preparation of t-butyl 4-chloro-7-ethyl-5-meth0xy-2- methylindole-3-carboxylate Treatment of t-butyl 4-chloro 7 ethyl-S-hydroxy-Z- methylindole-3-carboxylate (Ex. 114) with dimethylsulfate by the procedure described in Example 2, gives t-butyl 4-chloro-7-ethyl-S-methoxy-Z-methylindole in 84% yield, melting point 145-147 C.

EXAMPLE 116 Preparation of 4-chloro-7ethyl-5-methoxy-2-methylindole Treatment of t-butyl 4 chloro-7-ethyl-5-methoxy-2- methylindole-3-carboxylate (Ex. 115) with p-toluenesulfonic acid by the procedure described in Example 14 gives 4-chloro-7-ethyl-5-methoxy-2-methylindole in 78% yield. Recrystallization of a sample from ether-petroleum ether (30 cc.) furnishes near white crystals, melting point 90-9 1 C. A max 278 Ill 1. (6 11,150); 2.95, 3.4, 6.25 1.

EXAMPLE 117 Preparation of 7-ethyl-5-methoxy-2-methylindole Catalytic deehlorination of 4-chloro-7-ethyl-5-methoxy- Z-methylindole (Example 116) by the procedure of Example 10 furnishes 7-ethyl-S-methoxy-Z-methylindole in 90% yield, melting point of 70-72 C., recrystallization from ether-petroleum ether gives off-white crystals, melting point 7374 C. A max 215, 272, 292, 304 m (6 33,000, 9,850; 6,800, 4,380); 3.0, 3.4, 625

EXAMPLE 1 18 Preparation of 3-[7-(ethyl-5-methoxy-2-methyl-3-indolyl) ethyl] -3,3-aZabicy-clo [3 .2.2]nonane By the procedure of Example 16, 7-ethyl-5-methoxy-2- methylindole (Example 117) is treated with oxalyl chloride and the resulting 7-ethyl-5-methoxy-2-methylindole- 3-glyoxylic acid chloride is treated by the procedure of Example 16 with 3-azabicyclo[3.2.2]nonane to give the corresponding 3-glyoxamide derivative (melting point 190- 191 C.) which is then reduced with lithium aluminum hydride by the procedure of Example 66 to provide the subject compound as the maleate salt with melting point at 173-174 C. This compound shows a rod walking dose of 70 mg./kg.

14 EXAMPLE 119 Preparation of 3-[2-(5-methoxy-1,2,7-trimethyl-3-indolyl) ethyl]-3-azabicyclo[3.2.2]nonane A solution of 1.664 g. of 3-[2-(2,7-dimethyl-5-methoxy- 3-indolyl)ethyl]-3-azabicyclo[3.2.2]nonane (Example 86) in 10 ml. of dimethylsulfoxide is added to a cold solution of methylsulfinyl carbanion prepared from sodium hydride and dimethylsulfoxide. The resulting solution is stirred at room temperature for 1 hour, after which 725 mg. of methyl iodide is added. The reaction is stirred for 3 hours during which time a solid precipitates. This procedure gives 1.44 g. of off-white crystals, melting point 148- 152 C.

This compound shows activity as an analgesic and antiinflammatory agent.

EXAMPLE 120 Preparation of 5-methoxy-N,N-2-trimethyl-4-trifluoromethylindole-3-glyoxamide A solution of 2.0 ml. of oxalyl chloride in 20 ml. ether is added dropwise at 0 C. to a solution of 2.0 g. of 5- methoxy-Z-methyl-4-trifiuoromethylindole (Example 14) in 20 ml. of ether. The mixture is stirred at 0 for 1 hour then concentrated with a stream ofargon and filtered to give the intermediate glyoxalyl chloride as an orange powder.

The orange intermediate is suspended in ml. of ether and is agitated with a stream of anhydrous dimethylamine for one-half hour. The mixture is filtered and the residue is washed with water togive 2.27 g. of dimethylglyoxamide as pale yellow crystals, melting point 208- 211 C. The pure product, as white needles, melting point 211212 C. is obtained by crystallization from acetonehexane.

EXAMPLE 121 Preparation of 5-methoxy-N,N-2,4-tetramethyltryptamine succinate (A) A mixture of mg. of 5-methoxy-N,N-2,4tetramethylindole 3-glyoxamide (Example 19*) and 200 mg. of lithium aluminum hydride in 20 ml. of tetrahydrofuran is heated at reflux overnight. Water is added until the evolution of gas ceases. The inorganic precipitate is filtered and the filtrate is evaporated, dissolved in ether, Washed with water and again evaporated. The crude product, 140 mg. of yellow oil, is dissolved in 1 ml. of methanol and is added to a solution of 60 mg. of succinic acid in 2 ml. of methanol. After standing at room temperature for 1 hour, the solution is diluted with ether and the tetramethyltryptamine succinate is collected as white needles, melting point 134136 C.

(B) A mixture of 900 mg. of 5-methoxy-N,N-2-trimethyl-4-trifiuoromethylindole 3 glyoxamide (Example 120) and 1.0 g. of lithium aluminum hydride in 50 ml. of tetrahydrofuran is heated at reflux for 48 hours and is worked up as described in A above. The crude oil, 500 mg. is dissolved in 5 ml. of methanol and is mixed with 236 mg. of succinic acid in 3 ml. of methanol. After 1 hour at room temperature, the mixture is concentrated and diluted with ether. Filtration gives 340 mg. of white needles, melting point 132-134" C. which is identical with the tetramethyltryptarnine succinate obtained in A above.

We claim:

1. An indole selected from the group of the formula:

wherein R is a member selected from the group consisting of hydrogen and lower alkyl; R R and R are lower alkyl, R being substituted at the 4-, 6- or 7-positions of the indole nucleus; R is a member selected from the group consisting of lower alkyl, lower alkenyl, omegahydroxy lower alkyl and benzyl; R is a member selected from the group consisting of lower alkyl, lower alkenyl, omega-lower alkylthio lower alkyl, omega-hydroxy lower alkyl and 2,2,2-trifiuoroethyl and pharmaceutically acceptable acid addition salts.

2. The indole according to claim 1: 2,7-dimethy1-5- methoxy-N,N-diethyl tryptamine.

3. The indole according to claim 1: 2,7-dimethyl-5- methoxy N-(2-methyl-2-propenyl)tryptamine,

4. The indole according to claim 1: 2,7-dimethyl-5- methoxy-N-isopropyl, N-hydroxyethyl tryptamine.

5. The indole according to claim 1: 2,7-dimeth'yl-5- methoxy-N,N-dipropyltryptamine.

6. The indole according to claim 1: 2,6-dimethyl-5- methoxy-N- (2-meth'yl-2-propenyl) tryptamine.

7. The indole according to claim 1: 2,6-dimethy1-5- methoXy-N,N-dimethyltryptamine.

8. The indole according to claim 1: 2,4-dimethyl-5- methoxy-N,N-dirnethyltryptamine.

16 9. The indole according to claim 1: 2,6-dimethyl-5- ethoxy-N,N-dimethyltryptamine.

References Cited UNITED STATES PATENTS OTHER REFERENCES Nature, 190: 179-180 (1961), Gessner et al. J. Org. Chem. 23: 1977-1979 (1958), Benington et a1. CA. 63: 82960 (1965), Julia et a1.

HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner U.S. Cl. X.R.

20 260-29361, 247.5 B, 293.54, 296 B, 243 B, 326.13,

- UNITE Swifts":firENr-oFflCE CERTIFICATE OF CURREQTIUN' Patent No. 3, 6, 3 V Dated August 22, 97

Inventor(s) John Frank Pol'etto, George Rodger Allen, Jr.

Ruddy Littell and Martin Joseph Weiss It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, Formula (IV), line 4 please change Column 8 Table II, lines 20-24 in the formula, please change H CO COCOR to read II 7 CH3 ll H 00 COCOR FORM (10-69) USCOMM-DC some-ps9 9 [1.5. GOVERNMENT PRNTING OFFICE? 969 O"35-334 UMTED' STATES PATENT otmtt EERMFMATE m QURREQ'MQN Patent No. 5, 3 Dated ugust 22,, 1972 Inventor(s) John Frank: Poletto, George Ilodger Allen, Jr. \l 2 Ruddy Littell and Martin Jose h Weiss 1 It is certified that ertor appears in the a ova-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 8, Table 11; line 53, please change the formula from to read If N n "4 Column .9, Table II-continued, line 4, please change 4- EC" to read +0 4-CH Signed and sealed this 9th day of January 1973.,

(SEAL) Attest:

EDWARD M,FLETCHER,JR. ROBERT GOTTSCHA LK Attesting Officer Commissioner of Patents F ORM PO-105O (10-69) us. eovlmmlm' rmmms ornc: um o-aae-au 

